CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is fixed-dose combination of antiviral drugs EFV, FTC, and TDF [see Microbiology 12.4)]. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyEfavirenz: The effect of EFV on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean max of EFV in subjects with CYP2B6 6/6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean max observed in subjects with CYP2B6 1/1 genotype. positive relationship between EFV concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 msec and 11.3 msec in subjects with CYP2B66/6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions 5.4)]. 12.3 Pharmacokinetics. Efavirenz, emtricitabine and tenofovir disoproxil fumarate: One efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is bioequivalent to one Sustiva tablet (600 mg) plus one EMTRIVA (R) capsule (200 mg) plus one VIREAD (R) tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45). Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately to hours and steady-state plasma concentrations were reached in to 10 days. In 35 HIV-1 infected subjects receiving EFV 600 mg once daily, steady-state max was 12.9 +- 3.7 uM (mean +- SD), min was 5.6 +- 3.2 uM, and AUC was 184 +- 73 uM.hr. EFV is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labeled EFV, 14 to 34% of the dose was recovered in the urine (mostly as metabolites) and 16 to 61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for EFV metabolism. EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism. EFV has terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. Emtricitabine: Following oral administration, FTC is rapidly absorbed, with peak plasma concentrations occurring at to hours postdose. Following multiple dose oral administration of FTC to 20 HIV-1 infected subjects, the steady-state plasma FTC max was 1.8 +- 0.7 mcg/mL (mean +- SD) and the AUC over 24-hour dosing interval was 10.0 +- 3.1 mcgohr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 mcg/mL. The mean absolute bioavailability of FTC was 93%. Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02 to 200 mcg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3-sulfoxide diastereomers and their glucuronic acid conjugate. FTC is eliminated by combination of glomerular filtration and active tubular secretion with renal clearance in adults with normal renal function of 213 +- 89 mL/min (mean +- SD). Following single oral dose, the plasma FTC half-life is approximately 10 hours. Tenofovir DF: Following oral administration of single 300 mg dose of TDF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (C max) were achieved in 1.0 +- 0.4 hrs (mean +- SD) and max and AUC values were 296 +- 90 ng/mL and 2287 +- 685 ngohr/mL, respectively. The oral bioavailability of tenofovir from TDF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by combination of glomerular filtration and active tubular secretion, with renal clearance in adults with normal renal function of 243 +- 33 mL/min (mean +- SD). Following single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours. Effects of Food on Oral Absorption Efavirenz, emtricitabine and tenofovir disoproxil fumarate has not been evaluated in the presence of food. Administration of EFV tablets with high-fat meal increased the mean AUC and max of EFV by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of TDF and FTC in combination with either high-fat meal or light meal increased the mean AUC and max of tenofovir by 35% and 15%, respectively, without affecting FTC exposures [see Dosage and Administration 2.2) and Patient Counseling Information 17)] Specific Populations Race Efavirenz: The pharmacokinetics of EFV in HIV-1 infected subjects appear to be similar among the racial groups studied. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC. Tenofovir DF: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of TDF. Gender Efavirenz, Emtricitabine, and Tenofovir DF: EFV, FTC, and tenofovir pharmacokinetics are similar in male and female subjects. Pediatric Patients Efavirenz: In an open-label trial in NRTI-experienced pediatric subjects (mean age years, range to 16 years), the pharmacokinetics of EFV in pediatric subjects were similar to the pharmacokinetics in adults who received 600 mg daily dose of EFV. Based on mean steady-state predicted population pharmacokinetic modeling in pediatric subjects weighing >40 kg receiving the 600 mg dose of EFV, max was 6.57 mcg/mL, min was 2.82 mcg/mL, and AUC (0 to 24) was 254.78 uMohr. Emtricitabine: The pharmacokinetics of FTC at steady state were determined in 27 HIV-1 infected pediatric subjects 13 to 17 years of age receiving daily dose of mg/kg up to maximum dose of 240 mg oral solution or 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg capsule. Mean +- SD Cmax and AUC were 2.7 +- 0.9 mcg/mL and 12.6 +- 5.4 mcgohr/mL, respectively. Exposures achieved in pediatric subject 12 to less than 18 years of age were similar to those achieved in adults receiving once daily dose of 200 mg. Tenofovir DF: Steady-state pharmacokinetics of tenofovir were evaluated in HIV-1 infected pediatric subjects (12 to less than 18 years). Mean +- SD max and AUC tau are 0.38 +- 0.13 mcg/mL and 3.39 +- 1.22 mcgohr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of TDF 300 mg was similar to exposures achieved in adults receiving once-daily doses of TDF 300 mg. Geriatric Patients Pharmacokinetics of EFV, FTC, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations 8.5)]. Patients with Impaired Renal Function Efavirenz: The pharmacokinetics of EFV have not been studied in subjects with renal insufficiency; however, less than 1% of EFV is excreted unchanged in the urine, so the impact of renal impairment on EFV elimination should be minimal. Emtricitabine and Tenofovir DF: The pharmacokinetics of FTC and TDF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min, max and AUC 0- of FTC and tenofovir were increased [see Warnings and Precautions 5.7)]. Patients with Hepatic Impairment Efavirenz: multiple-dose trial showed no significant effect on EFV pharmacokinetics in subjects with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class or C) affects EFV pharmacokinetics [see Warnings and Precautions 5.3) and Use in Specific Populations 8.7)]. Emtricitabine: The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. Tenofovir DF: The pharmacokinetics of tenofovir following 300 mg dose of TDF have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. Assessment of Drug Interactions The drug interaction trials described were conducted with either efavirenz, emtricitabine and tenofovir disoproxil fumarate or the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets (EFV, FTC, or TDF) as individual agents. Efavirenz: The steady-state pharmacokinetics of EFV and tenofovir were unaffected when EFV and TDF were administered together versus each agent dosed alone. Specific drug interaction trials have not been performed with EFV and NRTIs other than tenofovir, lamivudine, and zidovudine. Clinically significant interactions would not be expected based on NRTIs elimination pathways. Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that EFV inhibited CYP isozymes 2C9 and 2C19 with i values (8.5 to 17 uM) in the range of observed EFV plasma concentrations. In in vitro studies, EFV did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K values 82 to 160 uM) only at concentrations well above those achieved clinically. Coadministration of EFV with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of EFV resulting in lowered plasma concentrations. Drug interaction trials were performed with EFV and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between EFV and zidovudine, lamivudine, azithromycin, fluconazole, lorazepam, cetirizine, or paroxetine. Single doses of famotidine or an aluminum and magnesium antacid with simethicone had no effects on EFV exposures. The effects of coadministration of EFV on max, AUC, and min are summarized in Table (effect of other drugs on EFV) and Table (effect of EFV on other drugs) see [Drug Interactions 7)]. Table Drug Interactions: Changes in Pharmacokinetic Parameters for EFV in the Presence of the Coadministered Drug Mean Change of EFV PharmacokineticParameters (90% CI) CoadministeredDrugDose ofCoadministeredDrug (mg) EFV Dose(mg)NC max AUCC min Lopinavir/ ritonavir 400/100 mg q12h 9 days 600 mg qd 9 days 11, 12 <-> 16 38 to 15) 16 42 to 20) Nelfinavir 750 mg q8h 7 days 600 mg qdx days 10 12 32 to 13) 12 35 to 18) 21 53 to 33) Ritonavir 500 mg q12h 8 days 600 mg qdx 10 days 14 4 to 26) 21 10 to 34) 25 7 to 46) Boceprevir 800 mg tid 6 days 600 mg qd 16 days NA 11 2 to 20) 20 15 to 26) NA Rifabutin 300 mg qd 14 days 600 mg qdx 14 days 11 <-> <-> 12 24 to 1) Rifampin 600 mg 7 days 600 mg qd 7 days 12 20 11 to 28) 26 15 to 36) 32 15 to 46) Artemether/ lumefantrine Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over days) 600 mg qd 26 days 12 <-> 17 NA Simvastatin 40 mg qd 4 days 600 mg qd 15 days 14 12 28 to 8) <-> 12 25 to 3) Carbamazepine 200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 15 days 600 mg qd 35 days 14 21 15 to 26) 36 32 to 40) 47 41 to 53) Diltiazem 240 mg 14 days 600 mg qd 28 days 12 16 6 to 26) 11 5 to 18) 13 1 to 26) Voriconazole 400 mg po q12h x1 day then 200 mg po q12h 8 days 400 mg qd 9 days NA 38 44 NA 300 mg po q12h days 2-7 300 mg qd 7 days NA 14 ( to 21) <-> NA 400 mg po q12h days 2-7 300 mg qd 7 days NA <-> 17 ( to 29) NA NA not available a. Increase ; Decrease ; No Effect <-> b. Parallel-group design; for EFV lopinavir/ritonavir, for EFV alone. c. 95% CI d. 90% CI not available e. Relative to steady-state administration of EFV (600 mg once daily for days). No effect on the pharmacokinetic parameters of EFV was observed with the following coadministered drugs: indinavir, saquinavir soft gelatin capsule, simeprevir, ledipasvir/sofosbuvir, sofosbuvir, clarithromycin, itraconazole, atorvastatin, pravastatin, or sertraline. Table Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of EFV Mean Change ofCoadministered DrugPharmacokinetic Parameters (90% CI)CoadministeredDrugDose ofCoadministeredDrug (mg) EFV Dose (mg) NC max AUCC min Atazanavir 400 mg qd with light meal 1-20 600 mg qd with light meal 7-20 27 59 49 to 67) 74 68 to 78) 93 90 to 95) 400 mg qd 1-6, then 300 mg qd 7-20 with ritonavir 100 mg qd and light meal 600 mg qd h after atazanavir and ritonavir 7-20 13 14 (17 to 58) 39 ( to 88) 48 ( 24 to 76) 300 mg qd/ritonavir 100 mg qd 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd 11-24 (pm) (simultaneous with EFV) 600 mg qd with light snack 11-24 (pm) 14 17 8 to 27) <-> 42 31 to 51) Indinavir 1000 mg q8h 10 days 600 mg qd 10 days 20 After morning dose <-> 33 ( 26 to 39) 39 ( 24 to 51) After afternoon dose <-> 37 ( 26 to 46) 52 ( 47 to 57) After evening dose 29 ( 11 to 43) 46 ( 37 to 54) 57 ( 50 to 63) Lopinavir/ ritonavir 400/100 mg q12h 9 days 600 mg qd 9 days 11, d <-> 19 ( 36 to 3) 39 ( to 62) Nelfinavir Metabolite AG-1402 750 mg q8h 7 days 600 mg qd 7 days 10 21 10 to 33) 40 30 to 48) 20 8 to 34) 37 25 to 48) <-> 43 21 to 59) Ritonavir 500 mg q12h 8 days 600 mg qd 10 days 11 After AM dose 24 (12 to 38) 18 6 to 33) 42 9 to 86) After PM dose <-> <-> 24 3 to 50) Saquinavir SGC 1200 mg q8h 10 days 600 mg qd 10 days 12 50 28 to 66) 62 45 to 74) 56 16 to 77) Maraviroc 100 mg bid 600 mg qd 12 51 37 to 62) 45 38 to 51) 45 28 to 57) Raltegravir 400 mg single dose 600 mg qd 36 2 to 59) 36 20 to 48) 21 51 to 28) Boceprevir 800 mg tid 6 days 600 mg qd 16 days NA ( 22 to 8) 19 11 to 25) 44 26 to 58) Simeprevir 150 mg qd 14 days 600 mg qd 14 days 23 51 46 to 56) 71 67 to 74) 91 88 to 92) Ledipasvir/ sofosbuvir Ledipasvir Sofosbuvir GS-331007 90/400 mg qd 14 days 600 mg qd 14 days 15 34 25 to 41) <-> <-> 34 25 to 41) <-> <-> 34 24 to 43) NA <-> Sofosbuvir GS-331007 400 mg qd single dose 600 mg qd 14 days 16 19 40 to 10) 23 16 to 30) <-> 16 24 to 8) NA NA Sofosbuvir/ velpatasvir nSofosbuvir GS-331007 Velpatasvir 400/100 mg qd 14 days 600 mg qd 14 days 14 38 14 to 67) 14 20 to 7) 47 57 to 36) <-> <-> 53 61 to 43) NA <-> 57 64 to 48) Clarithromycin 14-OH metabolite 500 mg q12h 7 days 400 mg qd 7 days 11 26 15 to 35) 49 32 to 69) 39 30 to 46) 34 18 to 53) 53 42 to 63) 26 9 to 45) Itraconazole Hydroxy- itraconazole 200 mg q12h 28 days 600 mg qd 14 days 18 37 20 to 51) 35 12 to 52) 39 21 to 53) 37 14 to 55) 44 27 to 58) 43 18 to 60) Posaconazole 400 mg (oral suspension) bid 10 and 20 days 400 mg qd 10 and 20 days 11 45 34 to 53) 50 40 to 57) NA Rifabutin 300 mg qd 14 days 600 mg qd 14 days 32 15 to 46) 38 28 to 47) 45 31 to 56) Artemether/ lumefantrine Artemether dihydroartemisinin lumefantrine Artemether20 mg/ lumefantrine120 mg tablets (6 4-tablet doses over days) 600 mg qd 26 days 12 21 38 <-> 51 46 21 NA NA NA Atorvastatin Total active (including metabolites) 10 mg qd 4 days 600 mg qd 15 days 14 14 (1 to 26) 15 2 to 26) 43 34 to 50) 32 21 to 41) 69 49 to 81) 48 23 to 64) Pravastatin 40 mg qd 4 days 600 mg qd 15 days 13 32 59 to 12) 44 26 to 57) 19 0 to 35) Simvastatin Total active (including metabolites) 40 mg qd 4 days 600 mg qd 15 days 14 72 63 to 79) 68 55 to 78) 68 62 to 73) 60 52 to 68) 45 20 to 62) NA Carbamazepine Epoxide metabolite 200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 29 days 600 mg qd 14 days 12 20 15 to 24) <-> 27 20 to 33) <-> 35 24 to 44) 13 30 to 7) Diltiazem Desacetyl diltiazem N-monodesmethyl diltiazem 240 mg 21 days 600 mg qd 14 days 13 60 50 to 68) 64( 57 to 69) 28 7 to 44) 69 55 to 79) 75 59 to 84) 37 17 to 52) 63 44 to 75) 62 44 to 75) 37 17 to 52) Ethinyl estradiol/ norgestimate Ethinyl estradiol Norelgestromin Levonorgestrel 0.035 mg/ 0.25 mg 14 days 600 mg qd 14 days 21 <-> <-> <-> 21 46 39 to 52) 64 62 to 67) 82 79 to 85) 80 77 to 83) 83 79 to 87) 86 80 to 90) Methadone Stable maintenance 35-100 mg daily 600 mg qd 14-21 days 11 45 25 to 59) 52 33 to 66) NA Bupropion Hydroxybupropion 150 mg single dose (sustained-release) 600 mg qd 14 days 13 34 21 to 47) 50 20 to 80) 55 48 to 62) <-> NA NA Sertraline 50 mg qd 14 days 600 mg qd 14 days 13 29 15 to 40) 39 27 to 50) 46 31 to 58) 400 mg po q12h 1 day then 200 mg po q12h 8 days 400 mg qd 9 days NA 61 77 NA 300 mg po q12h days 2-7 300 mg qd 7 days NA 36 ( 21 to 49) 55 ( 45 to 62) NA 400 mg po q12h days 2-7 300 mg qd 7 days NA 23 ( to 53) j 23 to 13) NA NA not available a. Increase =; Decrease ; No Effect <-> b. Compared with atazanavir 400 mg qd alone. c. Comparator dose of indinavir was 800 mg q8h 10 days. d. Parallel-group design; for EFV lopinavir/ritonavir, for lopinavir/ritonavir alone. e. Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent EFV. f. 95% CI g. Soft Gelatin Capsule h. Not available because of insufficient data. i. 90% CI not available. j. Relative to steady-state administration of voriconazole (400 mg for day, then 200 mg po q12h for days). k. Study conducted with efavirenz, emtricitabine and tenofovir disoproxil fumarate coadministered with HARVONI. l. The predominant circulating nucleoside metabolite of sofosbuvir. m. Study conducted with efavirenz, emtricitabine and tenofovir disoproxil fumarate coadministered with SOVALDI (R) (sofosbuvir). n. Study conducted with efavirenz, emtricitabine and tenofovir disoproxil fumarate coadministered with EPCLUSA. Emtricitabine and Tenofovir DF: The steady-state pharmacokinetics of FTC and tenofovir were unaffected when FTC and TDF were administered together versus each agent dosed alone. In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving FTC and tenofovir with other medicinal products is low. TDF is substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed. No clinically significant drug interactions have been observed between FTC and famciclovir, indinavir, sofosbuvir/velpatasvir, stavudine, TDF, and zidovudine. Similarly, no clinically significant drug interactions have been observed between TDF and abacavir, EFV, FTC, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, sofosbuvir, or tacrolimus in trials conducted in healthy volunteers. Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating lack of clinically significant drug interactions between these agents and TDF. The effects of coadministered drugs on the max, AUC, and min of tenofovir are shown in Table 6. The effects of coadministration of TDF on max, AUC, and Cmin of coadministered drugs are shown in Table 7. Table Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drug a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Change of Tenofovir PharmacokineticParameters (90% CI) max AUC min Atazanavir 400 once daily 14 days 33 14 8 to 20) 24 21 to 28) 22 15 to 30) Atazanavir/ ritonavir 300/100 once daily 12 34 20 to 51) 37 30 to 45) 29 21 to 36) Darunavir/ ritonavir 300/100 twice daily 12 24 8 to 42) 22 10 to 35) 37 19 to 57) Didanosine 250 or 400 once daily 7 days 14 <-> <-> <-> Ledipasvir/ sofosbuvir 90/400 once daily 15 79 56 to 104) 98 77 to 123) 163 (132 to 197) Lopinavir/ ritonavir 400/100 twice daily 14 days 24 <-> 32 25 to 38) 51 37 to 66) Sofosbuvir 400 once daily 16 25 8 to 45) <-> <-> Sofosbuvir/ velpatasvir 400/100 once daily 15 77 53 to 104) 81 68 to 94) 121 100 to 143) Tipranavir/ ritonavir 500/100 twice daily 22 23 (32 to 13) (9 to 5) (2 to 17) 750/200 twice daily (23 doses) 20 38 (46 to 29) (6 to 10) 14 (1 to 27) a. All interaction trials conducted in healthy volunteers. b. Subjects received TDF 300 mg once daily. c. Increase ; Decrease ; No Effect <-> d. Reyataz Prescribing Information. e. Prezista Prescribing Information. f. Subjects received didanosine buffered tablets. g. Aptivus Prescribing Information. Table Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TDF a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Change of Coadministered Drug Pharmacokinetic Parameters (90% CI) max AUC min Atazanavir 400 once daily 14 days 34 21 27 to 14) 25 30 to 19) 40 48 to 32) Atazanavir/ritonavir 300/100 once daily 42 days 10 28 50 to 5) 25 ( 42 to 3) 23 ( 46 to 10) Darunavirf Darunavir/ritonavir 300/100 once daily 12 16 (6 to 42) 21 (5 to 54) 24 (10 to 69) Didanosine 250 once, simultaneously with TDF and light meal 33 20 ( 32 to 7) <-> NA Lopinavir Ritonavir Lopinavir/ritonavir 400/100 twice daily 14 days 24 <-> <-> <-> Lopinavir/ritonavir 400/100 twice daily 14 days 24 <-> <-> <-> Tipranavir Tipranavir/ritonavir 500/100 twice daily 22 17 (26 to 6) 18 (25 to 9) 21 (30 to10) Tipranavir/ritonavir 750/200 twice daily (23 doses) 20 11 (16 to 4) (15 to 3) 12 (22 to 0) a. All interaction trials conducted in healthy volunteers. b. Subjects received TDF 300 mg once daily. c. Increase ; Decrease ; No Effect <-> d. Reyataz Prescribing Information. e. In HIV-infected patients, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. f. Prezista Prescribing Information. g. Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules. h. 373 kcal, 8.2 fat. i. Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. j. Aptivus Prescribing Information. 12.4 Microbiology. Mechanism of ActionEfavirenz: EFV is non-nucleoside reverse transcriptase (RT) inhibitor of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 RT and human cellular DNA polymerases , and are not inhibited by EFV. Emtricitabine: Emtricitabine, synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form FTC 5-triphosphate. Emtricitabine 5-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5-triphosphate is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase Tenofovir DF: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase Antiviral ActivityEfavirenz, Emtricitabine, and Tenofovir DF: In combination studies evaluating the antiviral activity in cell culture of FTC and EFV together, EFV and tenofovir together, and FTC and tenofovir together, additive to synergistic antiviral effects were observed. Efavirenz: The concentration of EFV inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90 to 95% (EC 90 to 95) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. Efavirenz demonstrated additive antiviral activity against HIV-1 in cell culture when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), protease inhibitors (PIs) (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz demonstrated antiviral activity against clade and most non-clade isolates (subtypes A, AE, AG, C, D, F, G, J, and N), but had reduced antiviral activity against group viruses. Efavirenz is not active against HIV-2. Emtricitabine: The antiviral activity in cell culture of FTC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC 50) values for FTC were in the range of 0.0013 to 0.64 uM (0.0003 to 0.158 mcg/mL). In drug combination studies of FTC with NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, EFV, and nevirapine), and PIs (amprenavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC 50 values ranged from 0.007 to 0.075 uM) and showed strain-specific activity against HIV-2 (EC 50 values ranged from 0.007 to 1.5 uM). Tenofovir DF: The antiviral activity in cell culture of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04 to 8.5 uM. In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, EFV, and nevirapine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and (EC 50 values ranged from 0.5 to 2.2 uM) and showed strain-specific activity against HIV-2 (EC 50 values ranged from 1.6 to 5.5 uM). ResistanceEFV, FTC, and TDF: HIV-1 isolates with reduced susceptibility to the combination of FTC and tenofovir have been selected in cell culture and in clinical trials. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT. In addition, K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in reduced susceptibility to tenofovir. In clinical trial of treatment-naive subjects [Study 934, see Clinical Studies (14)] resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuations. Genotypic resistance to EFV, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to EFV occurred in 13/19 analyzed subjects in the FTC TDF group and in 21/29 analyzed subjects in the zidovudine/lamivudine fixed-dose combination group. The M184V amino acid substitution, associated with resistance to FTC and lamivudine, was observed in 2/19 analyzed subject isolates in the FTC TDF group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects developed detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis. In clinical trial of treatment-naive subjects, isolates from 8/47 (17%) analyzed subjects receiving TDF developed the K65R substitution through 144 weeks of therapy; of these occurred in the first 48 weeks of treatment and one at Week 96. In treatment experienced subjects, 14/304 (5%) of TDF treated subjects with virologic failure through Week 96 showed greater than 1.4-fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed substitution in the HIV-1 RT gene resulting in the K65R amino acid substitution.Efavirenz: Clinical isolates with reduced susceptibility in cell culture to EFV have been obtained. The most frequently observed amino acid substitution in clinical trials with EFV is K103N (54%). One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, 227, and 230 were observed in subjects failing treatment with EFV in combination with other antiretrovirals. Other resistance substitutions observed to emerge commonly included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%). HIV-1 isolates with reduced susceptibility to EFV (greater than 380-fold increase in EC 90 value) emerged rapidly under selection in cell culture. Genotypic characterization of these viruses identified substitutions resulting in single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in RT. Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in clinical trials. Genotypic analysis of these isolates showed that the reduced susceptibility to FTC was associated with substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I). Tenofovir DF: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed K65R substitution in RT and showed 2- to 4-fold reduction in susceptibility to tenofovir. Cross ResistanceEfavirenz, Emtricitabine, and Tenofovir DF: Cross resistance has been recognized among NNRTIs. Cross resistance has also been recognized among certain NRTIs. The M184V/I and/or K65R substitutions selected in cell culture by the combination of FTC and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or FTC, and either abacavir or didanosine. Therefore, cross resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions. Efavirenz: Clinical isolates previously characterized as EFV resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to EFV in cell culture. Greater than 90% of NRTI-resistant isolates tested in cell culture retained susceptibility to EFV. Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross resistant to lamivudine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, EFV, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) or didanosine (L74V) remained sensitive to FTC. Tenofovir DF: Cross resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir, or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to FTC and lamivudine. Therefore, cross resistance among these drugs may occur in patients whose virus harbors the K65R substitution. The K70E substitution selected clinically by TDF results in reduced susceptibility to abacavir, didanosine, FTC, and lamivudine. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed mean of zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to TDF. Limited data are available for patients whose virus expressed Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had reduced response.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions 5.1)]. Rash [see Warnings and Precautions 5.2)]. Hepatotoxicity [see Warnings and Precautions 5.3)]. Psychiatric Symptoms [see Warnings and Precautions 5.5)]. Nervous System Symptoms [see Warnings and Precautions 5.6)]. New Onset or Worsening Renal Impairment [see Warnings and Precautions 5.7)]. Embryo-Fetal Toxicity [see Warnings and Precautions 5.8)]. Bone Loss and Mineralization Defects [see Warnings and Precautions 5.9)]. Convulsions [see Warnings and Precautions 5.10)]. Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions 5.11)]. Immune Reconstitution Syndrome [see Warnings and Precautions 5.12)]. Fat Redistribution [see Warnings and Precautions 5.13)]. Most common adverse reactions (incidence greater than or equal to 10%) observed in an active-controlled clinical trial of EFV, FTC, and TDF are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Subjects Study 934 was an open-label active-controlled trial in which 511 antiretroviral-naive subjects received either FTC TDF administered in combination with EFV (N=257) or zidovudine (AZT)/lamivudine (3TC) administered in combination with EFV (N=254). The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934 include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous trials of the individual components (Table 1). Table Selected Adverse Reactions (Grades to 4) Reported in >=5% in Either Treatment Group in Study 934 (0 to 144 Weeks) FTC+TDF+EFV AZT/3TC+EFV N=257 N=254 Fatigue 9% 8% Depression 9% 7% Nausea 9% 7% Diarrhea 9% 5% Dizziness 8% 7% Upper respiratory tract infections 8% 5% Sinusitis 8% 4% Rash Event 7% 9% Headache 6% 5% Insomnia 5% 7% Anxiety 5% 4% Nasopharyngitis 5% 3% Vomiting 2% 5% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC TDF with EFV. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular. In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive efavirenz, emtricitabine and tenofovir disoproxil fumarate or to stay on their baseline regimen. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets when each was administered in combination with other antiretroviral agents.Efavirenz, Emtricitabine, or TDF In addition to the adverse reactions in Study 934 and Study 073, the following adverse reactions were observed in clinical trials of EFV, FTC, or TDF in combination with other antiretroviral agents. Efavirenz: The most significant adverse reactions observed in subjects treated with EFV were nervous system symptoms [see Warnings and Precautions 5.6)] psychiatric symptoms [see Warnings and Precautions 5.5)], and rash [see Warnings and Precautions 5.2)]. Selected adverse reactions of moderate-to-severe intensity observed in greater than or equal to 2% of EFV-treated subjects in two controlled clinical trials included pain, impaired concentration, abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus. Pancreatitis has also been reported, although causal relationship with EFV has not been established. Asymptomatic increases in serum amylase levels were observed in significantly higher number of subjects treated with EFV 600 mg than in control subjects. Skin discoloration has been reported with higher frequency among FTC-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Clinical Trials in Pediatric SubjectsEfavirenz: Assessment of adverse reactions is based on three pediatric clinical trials in 182 HIV-1 infected pediatric subjects who received EFV in combination with other antiretroviral agents for median of 123 weeks. The type and frequency of adverse reactions in the three trials were generally similar to that of adult subjects with the exception of higher incidence of rash, which was reported in 32% (59/182) of pediatric subjects compared to 26% of adults, and higher frequency of Grade or rash reported in 3% (6/182) of pediatric subjects compared to 0.9% of adults [see Warnings and Precautions 5.2)]. Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116). Tenofovir DF: In pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF (N=81) were consistent with those observed in clinical trials of TDF in adults [see Warnings and Precautions 5.9)]. Laboratory AbnormalitiesEfavirenz, Emtricitabine and Tenofovir DF: Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous trials (Table 2). Table Significant Laboratory Abnormalities Reported in >=1% of Subjects in Either Treatment Group in Study 934 (0 to 144 Weeks) FTC TDF EFV AZT/3TC EFV N=257 N=254 Any >= Grade Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L) (F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L) (F: >170 U/L) 3% 3% ALT (M: >215 U/L) (F: >170 U/L) 2% 3% Hemoglobin (<8.0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (>=3+) <1% 1% Neutrophils (<750/mm 3) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% a. From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC TDF with EFV. Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934. Hepatic Events: In Study 934, 19 subjects treated with EFV, FTC, and TDF and 20 subjects treated with EFV and fixed-dose zidovudine/lamivudine were hepatitis surface antigen or hepatitis antibody positive. Among these coinfected subjects, one subject (1/19) in the EFV, FTC, and TDF arm had elevations in transaminases to greater than five times ULN through 144 weeks. In the fixed-dose zidovudine/lamivudine arm, two subjects (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected subject discontinued from the trial due to hepatobiliary disorders [see Warnings and Precautions 5.3)]. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of EFV, FTC, or TDF. Because postmarketing reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Efavirenz:Cardiac Disorders Palpitations Ear and Labyrinth Disorders Tinnitus, vertigo Endocrine Disorders Gynecomastia Eye Disorders Abnormal vision Gastrointestinal Disorders Constipation, malabsorption General Disorders and Administration Site Conditions Asthenia Hepatobiliary Disorders Hepatic enzyme increase, hepatic failure, hepatitis Immune System Disorders Allergic reactions Metabolism and Nutrition Disorders Redistribution/accumulation of body fat [see Warnings and Precautions 5.13)], hypercholesterolemia, hypertriglyceridemia Musculoskeletal and Connective Tissue Disorders Arthralgia, myalgia, myopathy Nervous System Disorders Abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor Psychiatric Disorders Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia Respiratory, Thoracic and Mediastinal Disorders Dyspnea Skin and Subcutaneous Tissue Disorders Flushing, erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section. Tenofovir DF: Immune System Disorders Allergic reaction, including angioedema Metabolism and Nutrition Disorders Lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Gastrointestinal Disorders Pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT) Skin and Subcutaneous Tissue Disorders Rash Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions Asthenia The following adverse reactions, listed under the body system headings above, may occur as consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Efavirenz, emtricitabine and tenofovir disoproxil fumarate: One efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is bioequivalent to one Sustiva tablet (600 mg) plus one EMTRIVA (R) capsule (200 mg) plus one VIREAD (R) tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45). Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately to hours and steady-state plasma concentrations were reached in to 10 days. In 35 HIV-1 infected subjects receiving EFV 600 mg once daily, steady-state max was 12.9 +- 3.7 uM (mean +- SD), min was 5.6 +- 3.2 uM, and AUC was 184 +- 73 uM.hr. EFV is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labeled EFV, 14 to 34% of the dose was recovered in the urine (mostly as metabolites) and 16 to 61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for EFV metabolism. EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism. EFV has terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. Emtricitabine: Following oral administration, FTC is rapidly absorbed, with peak plasma concentrations occurring at to hours postdose. Following multiple dose oral administration of FTC to 20 HIV-1 infected subjects, the steady-state plasma FTC max was 1.8 +- 0.7 mcg/mL (mean +- SD) and the AUC over 24-hour dosing interval was 10.0 +- 3.1 mcgohr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 mcg/mL. The mean absolute bioavailability of FTC was 93%. Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02 to 200 mcg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3-sulfoxide diastereomers and their glucuronic acid conjugate. FTC is eliminated by combination of glomerular filtration and active tubular secretion with renal clearance in adults with normal renal function of 213 +- 89 mL/min (mean +- SD). Following single oral dose, the plasma FTC half-life is approximately 10 hours. Tenofovir DF: Following oral administration of single 300 mg dose of TDF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (C max) were achieved in 1.0 +- 0.4 hrs (mean +- SD) and max and AUC values were 296 +- 90 ng/mL and 2287 +- 685 ngohr/mL, respectively. The oral bioavailability of tenofovir from TDF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by combination of glomerular filtration and active tubular secretion, with renal clearance in adults with normal renal function of 243 +- 33 mL/min (mean +- SD). Following single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours. Effects of Food on Oral Absorption Efavirenz, emtricitabine and tenofovir disoproxil fumarate has not been evaluated in the presence of food. Administration of EFV tablets with high-fat meal increased the mean AUC and max of EFV by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of TDF and FTC in combination with either high-fat meal or light meal increased the mean AUC and max of tenofovir by 35% and 15%, respectively, without affecting FTC exposures [see Dosage and Administration 2.2) and Patient Counseling Information 17)] Specific Populations Race Efavirenz: The pharmacokinetics of EFV in HIV-1 infected subjects appear to be similar among the racial groups studied. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC. Tenofovir DF: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of TDF. Gender Efavirenz, Emtricitabine, and Tenofovir DF: EFV, FTC, and tenofovir pharmacokinetics are similar in male and female subjects. Pediatric Patients Efavirenz: In an open-label trial in NRTI-experienced pediatric subjects (mean age years, range to 16 years), the pharmacokinetics of EFV in pediatric subjects were similar to the pharmacokinetics in adults who received 600 mg daily dose of EFV. Based on mean steady-state predicted population pharmacokinetic modeling in pediatric subjects weighing >40 kg receiving the 600 mg dose of EFV, max was 6.57 mcg/mL, min was 2.82 mcg/mL, and AUC (0 to 24) was 254.78 uMohr. Emtricitabine: The pharmacokinetics of FTC at steady state were determined in 27 HIV-1 infected pediatric subjects 13 to 17 years of age receiving daily dose of mg/kg up to maximum dose of 240 mg oral solution or 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg capsule. Mean +- SD Cmax and AUC were 2.7 +- 0.9 mcg/mL and 12.6 +- 5.4 mcgohr/mL, respectively. Exposures achieved in pediatric subject 12 to less than 18 years of age were similar to those achieved in adults receiving once daily dose of 200 mg. Tenofovir DF: Steady-state pharmacokinetics of tenofovir were evaluated in HIV-1 infected pediatric subjects (12 to less than 18 years). Mean +- SD max and AUC tau are 0.38 +- 0.13 mcg/mL and 3.39 +- 1.22 mcgohr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of TDF 300 mg was similar to exposures achieved in adults receiving once-daily doses of TDF 300 mg. Geriatric Patients Pharmacokinetics of EFV, FTC, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations 8.5)]. Patients with Impaired Renal Function Efavirenz: The pharmacokinetics of EFV have not been studied in subjects with renal insufficiency; however, less than 1% of EFV is excreted unchanged in the urine, so the impact of renal impairment on EFV elimination should be minimal. Emtricitabine and Tenofovir DF: The pharmacokinetics of FTC and TDF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min, max and AUC 0- of FTC and tenofovir were increased [see Warnings and Precautions 5.7)]. Patients with Hepatic Impairment Efavirenz: multiple-dose trial showed no significant effect on EFV pharmacokinetics in subjects with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class or C) affects EFV pharmacokinetics [see Warnings and Precautions 5.3) and Use in Specific Populations 8.7)]. Emtricitabine: The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. Tenofovir DF: The pharmacokinetics of tenofovir following 300 mg dose of TDF have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. Assessment of Drug Interactions The drug interaction trials described were conducted with either efavirenz, emtricitabine and tenofovir disoproxil fumarate or the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets (EFV, FTC, or TDF) as individual agents. Efavirenz: The steady-state pharmacokinetics of EFV and tenofovir were unaffected when EFV and TDF were administered together versus each agent dosed alone. Specific drug interaction trials have not been performed with EFV and NRTIs other than tenofovir, lamivudine, and zidovudine. Clinically significant interactions would not be expected based on NRTIs elimination pathways. Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that EFV inhibited CYP isozymes 2C9 and 2C19 with i values (8.5 to 17 uM) in the range of observed EFV plasma concentrations. In in vitro studies, EFV did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K values 82 to 160 uM) only at concentrations well above those achieved clinically. Coadministration of EFV with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of EFV resulting in lowered plasma concentrations. Drug interaction trials were performed with EFV and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between EFV and zidovudine, lamivudine, azithromycin, fluconazole, lorazepam, cetirizine, or paroxetine. Single doses of famotidine or an aluminum and magnesium antacid with simethicone had no effects on EFV exposures. The effects of coadministration of EFV on max, AUC, and min are summarized in Table (effect of other drugs on EFV) and Table (effect of EFV on other drugs) see [Drug Interactions 7)]. Table Drug Interactions: Changes in Pharmacokinetic Parameters for EFV in the Presence of the Coadministered Drug Mean Change of EFV PharmacokineticParameters (90% CI) CoadministeredDrugDose ofCoadministeredDrug (mg) EFV Dose(mg)NC max AUCC min Lopinavir/ ritonavir 400/100 mg q12h 9 days 600 mg qd 9 days 11, 12 <-> 16 38 to 15) 16 42 to 20) Nelfinavir 750 mg q8h 7 days 600 mg qdx days 10 12 32 to 13) 12 35 to 18) 21 53 to 33) Ritonavir 500 mg q12h 8 days 600 mg qdx 10 days 14 4 to 26) 21 10 to 34) 25 7 to 46) Boceprevir 800 mg tid 6 days 600 mg qd 16 days NA 11 2 to 20) 20 15 to 26) NA Rifabutin 300 mg qd 14 days 600 mg qdx 14 days 11 <-> <-> 12 24 to 1) Rifampin 600 mg 7 days 600 mg qd 7 days 12 20 11 to 28) 26 15 to 36) 32 15 to 46) Artemether/ lumefantrine Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over days) 600 mg qd 26 days 12 <-> 17 NA Simvastatin 40 mg qd 4 days 600 mg qd 15 days 14 12 28 to 8) <-> 12 25 to 3) Carbamazepine 200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 15 days 600 mg qd 35 days 14 21 15 to 26) 36 32 to 40) 47 41 to 53) Diltiazem 240 mg 14 days 600 mg qd 28 days 12 16 6 to 26) 11 5 to 18) 13 1 to 26) Voriconazole 400 mg po q12h x1 day then 200 mg po q12h 8 days 400 mg qd 9 days NA 38 44 NA 300 mg po q12h days 2-7 300 mg qd 7 days NA 14 ( to 21) <-> NA 400 mg po q12h days 2-7 300 mg qd 7 days NA <-> 17 ( to 29) NA NA not available a. Increase ; Decrease ; No Effect <-> b. Parallel-group design; for EFV lopinavir/ritonavir, for EFV alone. c. 95% CI d. 90% CI not available e. Relative to steady-state administration of EFV (600 mg once daily for days). No effect on the pharmacokinetic parameters of EFV was observed with the following coadministered drugs: indinavir, saquinavir soft gelatin capsule, simeprevir, ledipasvir/sofosbuvir, sofosbuvir, clarithromycin, itraconazole, atorvastatin, pravastatin, or sertraline. Table Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of EFV Mean Change ofCoadministered DrugPharmacokinetic Parameters (90% CI)CoadministeredDrugDose ofCoadministeredDrug (mg) EFV Dose (mg) NC max AUCC min Atazanavir 400 mg qd with light meal 1-20 600 mg qd with light meal 7-20 27 59 49 to 67) 74 68 to 78) 93 90 to 95) 400 mg qd 1-6, then 300 mg qd 7-20 with ritonavir 100 mg qd and light meal 600 mg qd h after atazanavir and ritonavir 7-20 13 14 (17 to 58) 39 ( to 88) 48 ( 24 to 76) 300 mg qd/ritonavir 100 mg qd 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd 11-24 (pm) (simultaneous with EFV) 600 mg qd with light snack 11-24 (pm) 14 17 8 to 27) <-> 42 31 to 51) Indinavir 1000 mg q8h 10 days 600 mg qd 10 days 20 After morning dose <-> 33 ( 26 to 39) 39 ( 24 to 51) After afternoon dose <-> 37 ( 26 to 46) 52 ( 47 to 57) After evening dose 29 ( 11 to 43) 46 ( 37 to 54) 57 ( 50 to 63) Lopinavir/ ritonavir 400/100 mg q12h 9 days 600 mg qd 9 days 11, d <-> 19 ( 36 to 3) 39 ( to 62) Nelfinavir Metabolite AG-1402 750 mg q8h 7 days 600 mg qd 7 days 10 21 10 to 33) 40 30 to 48) 20 8 to 34) 37 25 to 48) <-> 43 21 to 59) Ritonavir 500 mg q12h 8 days 600 mg qd 10 days 11 After AM dose 24 (12 to 38) 18 6 to 33) 42 9 to 86) After PM dose <-> <-> 24 3 to 50) Saquinavir SGC 1200 mg q8h 10 days 600 mg qd 10 days 12 50 28 to 66) 62 45 to 74) 56 16 to 77) Maraviroc 100 mg bid 600 mg qd 12 51 37 to 62) 45 38 to 51) 45 28 to 57) Raltegravir 400 mg single dose 600 mg qd 36 2 to 59) 36 20 to 48) 21 51 to 28) Boceprevir 800 mg tid 6 days 600 mg qd 16 days NA ( 22 to 8) 19 11 to 25) 44 26 to 58) Simeprevir 150 mg qd 14 days 600 mg qd 14 days 23 51 46 to 56) 71 67 to 74) 91 88 to 92) Ledipasvir/ sofosbuvir Ledipasvir Sofosbuvir GS-331007 90/400 mg qd 14 days 600 mg qd 14 days 15 34 25 to 41) <-> <-> 34 25 to 41) <-> <-> 34 24 to 43) NA <-> Sofosbuvir GS-331007 400 mg qd single dose 600 mg qd 14 days 16 19 40 to 10) 23 16 to 30) <-> 16 24 to 8) NA NA Sofosbuvir/ velpatasvir nSofosbuvir GS-331007 Velpatasvir 400/100 mg qd 14 days 600 mg qd 14 days 14 38 14 to 67) 14 20 to 7) 47 57 to 36) <-> <-> 53 61 to 43) NA <-> 57 64 to 48) Clarithromycin 14-OH metabolite 500 mg q12h 7 days 400 mg qd 7 days 11 26 15 to 35) 49 32 to 69) 39 30 to 46) 34 18 to 53) 53 42 to 63) 26 9 to 45) Itraconazole Hydroxy- itraconazole 200 mg q12h 28 days 600 mg qd 14 days 18 37 20 to 51) 35 12 to 52) 39 21 to 53) 37 14 to 55) 44 27 to 58) 43 18 to 60) Posaconazole 400 mg (oral suspension) bid 10 and 20 days 400 mg qd 10 and 20 days 11 45 34 to 53) 50 40 to 57) NA Rifabutin 300 mg qd 14 days 600 mg qd 14 days 32 15 to 46) 38 28 to 47) 45 31 to 56) Artemether/ lumefantrine Artemether dihydroartemisinin lumefantrine Artemether20 mg/ lumefantrine120 mg tablets (6 4-tablet doses over days) 600 mg qd 26 days 12 21 38 <-> 51 46 21 NA NA NA Atorvastatin Total active (including metabolites) 10 mg qd 4 days 600 mg qd 15 days 14 14 (1 to 26) 15 2 to 26) 43 34 to 50) 32 21 to 41) 69 49 to 81) 48 23 to 64) Pravastatin 40 mg qd 4 days 600 mg qd 15 days 13 32 59 to 12) 44 26 to 57) 19 0 to 35) Simvastatin Total active (including metabolites) 40 mg qd 4 days 600 mg qd 15 days 14 72 63 to 79) 68 55 to 78) 68 62 to 73) 60 52 to 68) 45 20 to 62) NA Carbamazepine Epoxide metabolite 200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 29 days 600 mg qd 14 days 12 20 15 to 24) <-> 27 20 to 33) <-> 35 24 to 44) 13 30 to 7) Diltiazem Desacetyl diltiazem N-monodesmethyl diltiazem 240 mg 21 days 600 mg qd 14 days 13 60 50 to 68) 64( 57 to 69) 28 7 to 44) 69 55 to 79) 75 59 to 84) 37 17 to 52) 63 44 to 75) 62 44 to 75) 37 17 to 52) Ethinyl estradiol/ norgestimate Ethinyl estradiol Norelgestromin Levonorgestrel 0.035 mg/ 0.25 mg 14 days 600 mg qd 14 days 21 <-> <-> <-> 21 46 39 to 52) 64 62 to 67) 82 79 to 85) 80 77 to 83) 83 79 to 87) 86 80 to 90) Methadone Stable maintenance 35-100 mg daily 600 mg qd 14-21 days 11 45 25 to 59) 52 33 to 66) NA Bupropion Hydroxybupropion 150 mg single dose (sustained-release) 600 mg qd 14 days 13 34 21 to 47) 50 20 to 80) 55 48 to 62) <-> NA NA Sertraline 50 mg qd 14 days 600 mg qd 14 days 13 29 15 to 40) 39 27 to 50) 46 31 to 58) 400 mg po q12h 1 day then 200 mg po q12h 8 days 400 mg qd 9 days NA 61 77 NA 300 mg po q12h days 2-7 300 mg qd 7 days NA 36 ( 21 to 49) 55 ( 45 to 62) NA 400 mg po q12h days 2-7 300 mg qd 7 days NA 23 ( to 53) j 23 to 13) NA NA not available a. Increase =; Decrease ; No Effect <-> b. Compared with atazanavir 400 mg qd alone. c. Comparator dose of indinavir was 800 mg q8h 10 days. d. Parallel-group design; for EFV lopinavir/ritonavir, for lopinavir/ritonavir alone. e. Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent EFV. f. 95% CI g. Soft Gelatin Capsule h. Not available because of insufficient data. i. 90% CI not available. j. Relative to steady-state administration of voriconazole (400 mg for day, then 200 mg po q12h for days). k. Study conducted with efavirenz, emtricitabine and tenofovir disoproxil fumarate coadministered with HARVONI. l. The predominant circulating nucleoside metabolite of sofosbuvir. m. Study conducted with efavirenz, emtricitabine and tenofovir disoproxil fumarate coadministered with SOVALDI (R) (sofosbuvir). n. Study conducted with efavirenz, emtricitabine and tenofovir disoproxil fumarate coadministered with EPCLUSA. Emtricitabine and Tenofovir DF: The steady-state pharmacokinetics of FTC and tenofovir were unaffected when FTC and TDF were administered together versus each agent dosed alone. In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving FTC and tenofovir with other medicinal products is low. TDF is substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed. No clinically significant drug interactions have been observed between FTC and famciclovir, indinavir, sofosbuvir/velpatasvir, stavudine, TDF, and zidovudine. Similarly, no clinically significant drug interactions have been observed between TDF and abacavir, EFV, FTC, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, sofosbuvir, or tacrolimus in trials conducted in healthy volunteers. Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating lack of clinically significant drug interactions between these agents and TDF. The effects of coadministered drugs on the max, AUC, and min of tenofovir are shown in Table 6. The effects of coadministration of TDF on max, AUC, and Cmin of coadministered drugs are shown in Table 7. Table Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drug a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Change of Tenofovir PharmacokineticParameters (90% CI) max AUC min Atazanavir 400 once daily 14 days 33 14 8 to 20) 24 21 to 28) 22 15 to 30) Atazanavir/ ritonavir 300/100 once daily 12 34 20 to 51) 37 30 to 45) 29 21 to 36) Darunavir/ ritonavir 300/100 twice daily 12 24 8 to 42) 22 10 to 35) 37 19 to 57) Didanosine 250 or 400 once daily 7 days 14 <-> <-> <-> Ledipasvir/ sofosbuvir 90/400 once daily 15 79 56 to 104) 98 77 to 123) 163 (132 to 197) Lopinavir/ ritonavir 400/100 twice daily 14 days 24 <-> 32 25 to 38) 51 37 to 66) Sofosbuvir 400 once daily 16 25 8 to 45) <-> <-> Sofosbuvir/ velpatasvir 400/100 once daily 15 77 53 to 104) 81 68 to 94) 121 100 to 143) Tipranavir/ ritonavir 500/100 twice daily 22 23 (32 to 13) (9 to 5) (2 to 17) 750/200 twice daily (23 doses) 20 38 (46 to 29) (6 to 10) 14 (1 to 27) a. All interaction trials conducted in healthy volunteers. b. Subjects received TDF 300 mg once daily. c. Increase ; Decrease ; No Effect <-> d. Reyataz Prescribing Information. e. Prezista Prescribing Information. f. Subjects received didanosine buffered tablets. g. Aptivus Prescribing Information. Table Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TDF a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Change of Coadministered Drug Pharmacokinetic Parameters (90% CI) max AUC min Atazanavir 400 once daily 14 days 34 21 27 to 14) 25 30 to 19) 40 48 to 32) Atazanavir/ritonavir 300/100 once daily 42 days 10 28 50 to 5) 25 ( 42 to 3) 23 ( 46 to 10) Darunavirf Darunavir/ritonavir 300/100 once daily 12 16 (6 to 42) 21 (5 to 54) 24 (10 to 69) Didanosine 250 once, simultaneously with TDF and light meal 33 20 ( 32 to 7) <-> NA Lopinavir Ritonavir Lopinavir/ritonavir 400/100 twice daily 14 days 24 <-> <-> <-> Lopinavir/ritonavir 400/100 twice daily 14 days 24 <-> <-> <-> Tipranavir Tipranavir/ritonavir 500/100 twice daily 22 17 (26 to 6) 18 (25 to 9) 21 (30 to10) Tipranavir/ritonavir 750/200 twice daily (23 doses) 20 11 (16 to 4) (15 to 3) 12 (22 to 0) a. All interaction trials conducted in healthy volunteers. b. Subjects received TDF 300 mg once daily. c. Increase ; Decrease ; No Effect <-> d. Reyataz Prescribing Information. e. In HIV-infected patients, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. f. Prezista Prescribing Information. g. Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules. h. 373 kcal, 8.2 fat. i. Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. j. Aptivus Prescribing Information.

PREGNANCY SECTION.

8.1 Pregnancy. Antiretroviral Pregnancy Registry There is pregnancy exposure registry that monitors pregnancy outcomes in adults and adolescents exposed to efavirenz, emtricitabine and tenofovir disoproxil fumarate during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at (800) 258-4263. Risk Summary There are retrospective case reports of neural tube defects in infants whose mothers were exposed to EFV-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the APR are not sufficient to adequately assess this risk. Although causal relationship has not been established between exposure to EFV in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose (see Data). In addition, fetal and embryonic toxicities occurred in rats at dose 10 times less than the human exposure at the recommended clinical human dose (RHD) of EFV. Because of the potential risk of neural tube defects, EFV is not recommended for use in the first trimester of pregnancy. Avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and for 12 weeks after discontinuation. Advise pregnant patients of the potential risk to fetus. Available data from the APR show no increase in the overall risk of major birth defects for EFV, FTC, or TDF compared with the background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. The background risk of major birth defects and miscarriage for the indicated population is unknown. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates mothers and infants from limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation. In animal reproduction studies, no adverse developmental effects were observed when FTC and TDF were administered separately at doses/exposures >=60 (FTC), >=14 (TDF) and 2.7 (tenofovir) times those at the RHD of efavirenz, emtricitabine and tenofovir disoproxil fumarate (see Data). Data Human Data Efavirenz: There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to EFV-containing regimens in the first trimester. Based on prospective reports to the APR of 1,217 exposures to EFV-containing regimens during pregnancy resulting in live births (including over 1,023 live births exposed in the first trimester and 194 exposed in the second/third trimester), there was no increase in overall birth defects with EFV compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.5% to 3.5%) with first trimester exposure to EFV-containing regimens, and 1.5% (95% CI: 0.3% to 4.5%) with the second/third trimester exposure to EFV-containing regimens. One of these prospectively reported defects with first-trimester exposure was neural tube defect. single case of anophthalmia with first-trimester exposure to EFV has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have known association with anophthalmia. Emtricitabine: Based on prospective reports from the APR of 4,005 exposures to FTC- containing regimens during pregnancy resulting in live births (including 2,785 exposed in the first trimester and 1,220 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens. Tenofovir DF: Based on prospective reports from the APR of 5,105 exposures to TDF- containing regimens during pregnancy resulting in live births (including 3,535 exposed in the first trimester and 1,570 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to TDF- containing regimens, and 2.2% (95% CI: 1.6% to 3.1%) with the second/third trimester exposure to TDF-containing regimens. Animal Data Efavirenz: Effects of EFV on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, EFV 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation Days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposures at the RHD, with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, EFV was administered either during organogenesis (gestation Days to 18) or from gestation Day through lactation Day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with an increase in the incidence of early resorptions, and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the RHD. Drug concentrations in the milk on lactation Day 10 were approximately times higher than those in maternal plasma. In pregnant rabbits, EFV was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation Days through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the RHD. Emtricitabine: FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days through 15, and through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the RHD. In pre/postnatal development study in mice, FTC was administered orally at doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the RHD. Tenofovir DF: TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days through 17, and through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the RHD based on body surface area comparisons and in rabbits at doses up to 19 times the RHD based on body surface area comparisons. In pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the RHD.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Consult Full Prescribing Information prior to and during treatment for important potential drug interactions. 4, 5.4, 7) HIV-1 protease inhibitors: Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with either lopinavir/ritonavir or darunavir and ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with either atazanavir or atazanavir and ritonavir is not recommended. 7.3) 7.1 Efavirenz. Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with EFV. Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of EFV, resulting in lowered plasma concentrations [see Dosage and Administration 2.2)]. There is limited information available on the potential for pharmacodynamic interaction between EFV and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of EFV [see Clinical Pharmacology 12.2)]. Consider alternatives to efavirenz, emtricitabine and tenofovir disoproxil fumarate when coadministered with drug with known risk of Torsade de Pointes. 7.2 Drugs Affecting Renal Function. FTC and tenofovir are primarily eliminated by the kidneys [see Clinical Pharmacology 12.3)]. Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions 5.7)]. Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir. 7.3 Established and Potentially Significant Drug Interactions. Other important drug interaction information for efavirenz, emtricitabine and tenofovir disoproxil fumarate is summarized in Table 3. The drug interactions described are based on trials conducted with either efavirenz, emtricitabine and tenofovir disoproxil fumarate, the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets (EFV, FTC, or TDF) as individual agents, or are potential drug interactions [see Clinical Pharmacology 12.3)]. Table Established and Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: atazanavir atazanavir tenofovir Coadministration of atazanavir with efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended. The combined effect of EFV plus TDF on atazanavir plasma concentrations is not known. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with efavirenz, emtricitabine and tenofovir disoproxil fumarate. Protease inhibitor: fosamprenavir calcium amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and efavirenz, emtricitabine and tenofovir disoproxil fumarate with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz, emtricitabine and tenofovir disoproxil fumarate is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz, emtricitabine and tenofovir disoproxil fumarate is administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: indinavir indinavir The optimal dose of indinavir, when given in combination with EFV, is not known. Increasing the indinavir dose to 1000 mg every hours does not compensate for the increased indinavir metabolism due to EFV. Protease inhibitor: darunavir/ritonavir lopinavir/ritonavir tenofovir lopinavir tenofovir Monitor patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate concomitantly with ritonavir-boosted darunavir for TDF-associated adverse reactions. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients who develop TDF-associated adverse reactions. Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with EFV. Refer to the Full Prescribing Information for lopinavir/ritonavir for guidance on coadministration with EFV- or tenofovir-containing regimens, such as efavirenz, emtricitabine and tenofovir disoproxil fumarate. Patients should be monitored for tenofovir- associated adverse reactions. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients who develop TDF-associated adverse reactions. Protease inhibitor: ritonavir ritonavir efavirenz When ritonavir 500 mg every 12 hours was coadministered with EFV 600 mg once daily, the combination was associated with higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when efavirenz, emtricitabine and tenofovir disoproxil fumarate is used in combination with ritonavir. Protease inhibitor: saquinavir saquinavir Appropriate doses of the combination of EFV and saquinavir/ritonavir with respect to safety and efficacy have not been established. CCR5 co-receptor antagonist: maraviroc maraviroc Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz, emtricitabine and tenofovir disoproxil fumarate. NRTI: didanosine didanosine Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and didanosine should be monitored closely for didanosine-associated adverse reactions. Discontinue didanosine in patients who develop didanosine-associated adverse reactions. Higher didanosine concentrations could potentiate didanosine- associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving TDF with didanosine 400 mg daily. In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with efavirenz, emtricitabine and tenofovir disoproxil fumarate. In patients weighing less than 60 kg, reduce the didanosine dose to 200 mg when it is coadministered with efavirenz, emtricitabine and tenofovir disoproxil fumarate. When coadministered, efavirenz, emtricitabine and tenofovir disoproxil fumarate and Videx EC may be taken under fasted conditions or with light meal (less than 400 kcal, 20% fat). NNRTI: Other NNRTIs or efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. Efavirenz, emtricitabine and tenofovir disoproxil fumarate contains EFV and should not be coadministered with other NNRTIs. Integrase strand transfer inhibitor: raltegravir raltegravir The clinical significance of this interaction has not been directly assessed. Hepatitis antiviral agents boceprevir boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with EFV, which may result in loss of therapeutic effect. The combination should be avoided. elbasvir/grazoprevir elbasvir grazoprevir Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with elbasvir/grazoprevir is contraindicated [see Contraindications 4)] because it may lead to loss of virologic response to elbasvir/grazoprevir. glecaprevir/pibrentasvir glecaprevir pibrentasvir Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended because it may lead to reduced therapeutic effect of glecaprevir/pibrentasvir. ledipasvir/sofosbuvir tenofovir Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and HARVONI (R) (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with TDF. simeprevir simeprevir <-> efavirenz Concomitant administration of simeprevir with EFV is not recommended because it may result in loss of therapeutic effect of simeprevir. sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir tenofovir velpatasvir voxilaprevir Coadministration of EFV-containing regimens and EPCLUSA (R) (sofosbuvir/velpatasvir) or VOSEVI (R) (sofosbuvir/velpatasvir/voxilaprevir) is not recommended. Other agents Anticoagulant: warfarin or warfarin Plasma concentrations and effects potentially increased or decreased by EFV. Anticonvulsants: carbamazepine carbamazepine efavirenz There are insufficient data to make dose recommendation for efavirenz, emtricitabine and tenofovir disoproxil fumarate. Alternative anticonvulsant treatment should be used. phenytoin phenobarbital anticonvulsant efavirenz Potential for reduction in anticonvulsant and/or EFV plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. Antidepressants: bupropion bupropion The effect of EFV on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. sertraline sertraline Increases in sertraline dose should be guided by clinical response. Antifungals: itraconazole itraconazole hydroxy- itraconazole Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. ketoconazole ketoconazole Drug interaction trials with efavirenz, emtricitabine and tenofovir disoproxil fumarate and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. posaconazole posaconazole Avoid concomitant use unless the benefit outweighs the risks. voriconazole voriconazole efavirenz Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with voriconazole is contraindicated [see Contraindications 4)] because it may lead to reduced therapeutic effect of voriconazole and increased risk of EFV-associated adverse reactions Anti-infective: clarithromycin clarithromycin 14-OH metabolite Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation. Antimycobacterial: rifabutin rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given or times week. rifampin efavirenz If efavirenz, emtricitabine and tenofovir disoproxil fumarate is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of EFV is recommended. Antimalarials: artemether/ lumefantrine atovaquone/proguanil artemether dihydroartemisinin lumefantrine atovaquone proguanil Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation [see Warnings and Precautions 5.4)] Concomitant administration of atovaquone/proguanil with efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended. Calcium channel blockers: diltiazem diltiazem desacetyl diltiazem N-monodes- methyl diltiazem Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz, emtricitabine and tenofovir disoproxil fumarate is necessary when administered with diltiazem. Others e.g., felodipine nicardipine nifedipine verapamil calcium channel blocker No data are available on the potential interactions of EFV with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin atorvastatin pravastatin simvastatin Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with EFV. Consult the Full Prescribing Information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. Hormonal contraceptives: Oral: ethinyl estradiol/norgestimate Implant: etonogestrel active metabolites of norgestimate etonogestrel reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on EFV plasma concentrations was observed. reliable method of barrier contraception must be used in addition to hormonal contraceptives. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in EFV-exposed patients. Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by EFV. These immunosuppressants are not anticipated to affect exposure of EFV. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate. Narcotic analgesic: methadone methadone Coadministration of EFV in HIV-1 infected individuals with history of injection drug use resulted in signs of opiate withdrawal. Methadone dose was increased by mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. a. This table is not all inclusive. 7.4 Efavirenz Assay Interference. Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving EFV. Confirmation of positive screening tests for cannabinoids by more specific method is recommended.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV Inform patients that severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued FTC or TDF, and may occur with discontinuation of efavirenz, emtricitabine and tenofovir disoproxil fumarate. Advise patients not to discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate without first informing their healthcare provider. All patients should be tested for HBV infection before or when starting efavirenz, emtricitabine and tenofovir disoproxil fumarate and those who are infected with HBV need close medical follow-up for several months after stopping efavirenz, emtricitabine and tenofovir disoproxil fumarate to monitor for exacerbations of hepatitis [see Warnings and Precautions 5.1)]. Rash Inform patients that common side effect is rash, and that rashes usually go away without any change in treatment. However, since rash may be serious, advise patients to contact their physician promptly if rash occurs [see Warnings and Precautions 5.2)]. Hepatotoxicity Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur [see Warnings and Precautions 5.3) and Adverse Reactions 6.1)]. Drug Interactions Advise patients that efavirenz, emtricitabine and tenofovir disoproxil fumarate may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other medication, including other drugs for treatment of hepatitis virus [see Warnings and Precautions (5.4) and Drug Interactions 7)]. Psychiatric Symptoms Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms, and catatonia have been reported in patients receiving EFV, component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions 5.5)]. Advise patients to seek immediate medical evaluation if they experience severe psychiatric adverse experiences. Advise patients to inform their physician of any history of mental illness or substance abuse. Nervous System Symptoms Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams, are commonly reported during the first weeks of therapy with EFV, component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy. Alert patients to the potential for additive effects when efavirenz, emtricitabine and tenofovir disoproxil fumarate is used concomitantly with alcohol or psychoactive drugs. Instruct patients that if they experience NSS to avoid potentially hazardous tasks such as driving or operating machinery [see Warnings and Precautions 5.6) and Dosage and Administration 2.2)]. Inform patients that there is risk of developing late-onset neurotoxicity, including ataxia and encephalopathy, which may occur months to years after beginning therapy with EFV, component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions 5.6)]. New Onset or Worsening Renal Impairment Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Advise patients to avoid using efavirenz, emtricitabine and tenofovir disoproxil fumarate with concurrent or recent use of nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Warnings and Precautions 5.7)]. Embryo-Fetal Toxicity Apprise patients of the potential harm to the fetus if efavirenz, emtricitabine and tenofovir disoproxil fumarate is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug. Instruct adults and adolescents of childbearing potential receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate to avoid pregnancy and to notify their healthcare provider if they become pregnant or plan to become pregnant while taking efavirenz, emtricitabine and tenofovir disoproxil fumarate [see Warnings and Precautions 5.8)]. reliable form of barrier contraception must always be used in combination with other methods of contraception, including oral or other hormonal contraception. Because of the long half-life of EFV, recommend use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz, emtricitabine and tenofovir disoproxil fumarate [see Use in Specific Populations 8.1, 8.3)]. Bone Loss and Mineralization Defects Inform patients that decreases in bone mineral density have been observed with the use of TDF, component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Advise patients that bone mineral density monitoring may be performed in patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions 5.9)]. Convulsions Inform patients that convulsions have been reported with the use of EFV, component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver may require periodic monitoring of plasma levels [see Warnings and Precautions 5.10) and Drug Interactions 7.3)]. Lactic Acidosis and Severe Hepatomegaly Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions 5.11)]. Immune Reconstitution Syndrome Inform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the bodys immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions 5.12)]. Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including efavirenz, emtricitabine and tenofovir disoproxil fumarate and that the cause and long-term health effects of these conditions are not known [see Warnings and Precautions 5.13)]. Dosing Instructions Advise patients to take efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets orally on an empty stomach and that it is important to take efavirenz, emtricitabine and tenofovir disoproxil fumarate on regular dosing schedule to avoid missing doses. Advise patients that dosing at bedtime may improve the tolerability of nervous system symptoms [see Dosage and Administration 2.1)]. Pregnancy Registry Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to efavirenz, emtricitabine and tenofovir disoproxil fumarate during pregnancy [see Use in Specific Populations 8.1)]. Lactation Instruct patients not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations 8.2)]. All Brands listed are the registered trademarks of their respective owners and are not the trademarks of Annora Pharma Private Limited.Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 By: Annora Pharma Pvt. Ltd. Sangareddy 502313, Telangana, India. Revised: 01/2022. camberlogo1.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and for 12 weeks after discontinuation. 5.8, 8.3) Lactation: Breastfeeding is not recommended. 8.2) Females and Males of Reproductive Potential: Pregnancy testing and contraception are recommended. 8.3) Pediatrics: The incidence of rash was higher than in adults. 5.2, 6.1) 8.1 Pregnancy. Antiretroviral Pregnancy Registry There is pregnancy exposure registry that monitors pregnancy outcomes in adults and adolescents exposed to efavirenz, emtricitabine and tenofovir disoproxil fumarate during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at (800) 258-4263. Risk Summary There are retrospective case reports of neural tube defects in infants whose mothers were exposed to EFV-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the APR are not sufficient to adequately assess this risk. Although causal relationship has not been established between exposure to EFV in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose (see Data). In addition, fetal and embryonic toxicities occurred in rats at dose 10 times less than the human exposure at the recommended clinical human dose (RHD) of EFV. Because of the potential risk of neural tube defects, EFV is not recommended for use in the first trimester of pregnancy. Avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and for 12 weeks after discontinuation. Advise pregnant patients of the potential risk to fetus. Available data from the APR show no increase in the overall risk of major birth defects for EFV, FTC, or TDF compared with the background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. The background risk of major birth defects and miscarriage for the indicated population is unknown. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates mothers and infants from limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation. In animal reproduction studies, no adverse developmental effects were observed when FTC and TDF were administered separately at doses/exposures >=60 (FTC), >=14 (TDF) and 2.7 (tenofovir) times those at the RHD of efavirenz, emtricitabine and tenofovir disoproxil fumarate (see Data). Data Human Data Efavirenz: There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to EFV-containing regimens in the first trimester. Based on prospective reports to the APR of 1,217 exposures to EFV-containing regimens during pregnancy resulting in live births (including over 1,023 live births exposed in the first trimester and 194 exposed in the second/third trimester), there was no increase in overall birth defects with EFV compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.5% to 3.5%) with first trimester exposure to EFV-containing regimens, and 1.5% (95% CI: 0.3% to 4.5%) with the second/third trimester exposure to EFV-containing regimens. One of these prospectively reported defects with first-trimester exposure was neural tube defect. single case of anophthalmia with first-trimester exposure to EFV has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have known association with anophthalmia. Emtricitabine: Based on prospective reports from the APR of 4,005 exposures to FTC- containing regimens during pregnancy resulting in live births (including 2,785 exposed in the first trimester and 1,220 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens. Tenofovir DF: Based on prospective reports from the APR of 5,105 exposures to TDF- containing regimens during pregnancy resulting in live births (including 3,535 exposed in the first trimester and 1,570 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to TDF- containing regimens, and 2.2% (95% CI: 1.6% to 3.1%) with the second/third trimester exposure to TDF-containing regimens. Animal Data Efavirenz: Effects of EFV on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, EFV 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation Days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposures at the RHD, with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, EFV was administered either during organogenesis (gestation Days to 18) or from gestation Day through lactation Day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with an increase in the incidence of early resorptions, and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the RHD. Drug concentrations in the milk on lactation Day 10 were approximately times higher than those in maternal plasma. In pregnant rabbits, EFV was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation Days through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the RHD. Emtricitabine: FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days through 15, and through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the RHD. In pre/postnatal development study in mice, FTC was administered orally at doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the RHD. Tenofovir DF: TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days through 17, and through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the RHD based on body surface area comparisons and in rabbits at doses up to 19 times the RHD based on body surface area comparisons. In pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the RHD. 8.2 Lactation. Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Based on limited published data, EFV, FTC, and tenofovir have been shown to be present in human breast milk. It is not known if the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets affect milk production or have effects on the breastfed child. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate. 8.3 Females and Males of Reproductive Potential. Pregnancy Testing Perform pregnancy testing in adults and adolescents of childbearing potential before initiation of efavirenz, emtricitabine and tenofovir disoproxil fumarate because of potential risk of neural tube defects [see Use in Specific Populations 8.1)]. Contraception Advise adults and adolescents of childbearing potential to use effective contraception during treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate and for 12 weeks after discontinuing efavirenz, emtricitabine and tenofovir disoproxil fumarate due to the long half-life of EFV, component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Hormonal methods that contain progesterone may have decreased effectiveness. Always use barrier contraception in combination with other methods of contraception [see Drug Interactions 7.1, 7.3)]. 8.4 Pediatric Use. The effectiveness and safety of efavirenz, emtricitabine and tenofovir disoproxil fumarate as complete regimen for the treatment of HIV-1 infection was established in pediatric patients with body weight greater than or equal to 40 kg [see Dosage and Administration 2.2)]. Use of efavirenz, emtricitabine and tenofovir disoproxil fumarate in this age group is supported by adequate and well-controlled studies of efavirenz, emtricitabine and tenofovir disoproxil fumarate in adults with HIV-1 infection and data from pediatric studies of the individual components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets (EFV, FTC, and TDF). Efavirenz, emtricitabine and tenofovir disoproxil fumarate should only be administered to pediatric patients with body weight greater than or equal to 40 kg. Because efavirenz, emtricitabine and tenofovir disoproxil fumarate is fixed-dose combination tablet, the dose of efavirenz, emtricitabine and tenofovir disoproxil fumarate cannot be adjusted for patients of lower weight [see Warnings and Precautions 5.2, 5.9), Adverse Reactions 6.1), and Clinical Pharmacology 12.3)]. 8.5 Geriatric Use. Clinical trials of EFV, FTC, or TDF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.. 8.6 Renal Impairment. Because efavirenz, emtricitabine and tenofovir disoproxil fumarate is fixed-dose combination, and cannot be dose adjusted, it is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) [see Dosage and Administration 2.3), Warnings and Precautions 5.7)]. 8.7 Hepatic Impairment. Efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine an appropriate dose. Patients with mild hepatic impairment may be treated with efavirenz, emtricitabine and tenofovir disoproxil fumarate at the approved dose. Because of the extensive cytochrome P450-mediated metabolism of EFV and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering efavirenz, emtricitabine and tenofovir disoproxil fumarate to these patients [see Dosage and Administration 2.4), Warnings and Precautions 5.3), and Clinical Pharmacology 12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Rash: Discontinue if severe rash develops. 5.2, 6.1) Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis or coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, few occurred in patients with no pre-existing hepatic disease. 5.3, 6.2, 8.7) Risk of adverse reactions or loss of virologic response due to drug interactions: Consult full prescribing information prior to and during treatment for important potential drug interactions. Consider alternatives to efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients taking other medications with known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. 5.4) Serious psychiatric symptoms: Immediate medical evaluation is recommended. 5.5, 6.1) Nervous system symptoms (NSS): NSS are frequent, usually begin to days after initiating therapy, and resolve in to weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. 2.2, 5.6) New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Prior to initiation and during use of efavirenz, emtricitabine and tenofovir disoproxil fumarate, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Avoid administering efavirenz, emtricitabine and tenofovir disoproxil fumarate with concurrent or recent use of nephrotoxic drugs. 5.7) Embryo fetal toxicity: Fetal harm may occur when administered to pregnant woman during the first trimester. Avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and for 12 weeks after discontinuation. 5.8, 8.1) Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with history of pathological fracture or other risk factors for osteoporosis or bone loss. 5.9) Convulsions: Use caution in patients with history of seizures. 5.10) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. 5.11) Immune reconstitution syndrome: May necessitate further evaluation and treatment. 5.12) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. 5.13) 5.1 Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV. All patients should be tested for the presence of chronic HBV before or when initiating antiretroviral therapy [see Dosage and Administration 2.1)]. Severe acute exacerbations of hepatitis (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued FTC or TDF, two of the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Patients who are coinfected with HIV-1 and HBV should be closely monitored, with both clinical and laboratory follow-up for at least several months after stopping treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate. If appropriate, initiation of anti-hepatitis therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. 5.2 Rash. In controlled clinical trials, 26% (266/1,008) of adult subjects treated with 600 mg EFV experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1,008) of subjects treated with EFV. The incidence of Grade rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult subjects treated with EFV in all trials and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first weeks of initiating therapy with EFV (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with EFV, rash resolves within month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1,008). Efavirenz, emtricitabine and tenofovir disoproxil fumarate can be reinitiated in patients interrupting therapy because of rash. Efavirenz, emtricitabine and tenofovir disoproxil fumarate should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered [see Contraindications 4)]. Experience with EFV in subjects who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen subjects who discontinued nevirapine because of rash have been treated with EFV. Nine of these subjects developed mild-to-moderate rash while receiving therapy with EFV, and two of these subjects discontinued because of rash. Rash was reported in 59 of 182 pediatric subjects (32%) treated with EFV [see Adverse Reactions 6.1)] Two pediatric subjects experienced Grade rash (confluent rash with fever, generalized rash), and four subjects had Grade rash (erythema multiforme). The median time to onset of rash in pediatric subjects was 28 days (range to 1,642 days). Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz, emtricitabine and tenofovir disoproxil fumarate in pediatric patients should be considered. 5.3 Hepatotoxicity. Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported in patients treated with EFV, component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Reports have included patients with underlying hepatic disease, including coinfection with hepatitis or C, and patients without pre-existing hepatic disease or other identifiable risk factors [see Warnings and Precautions 5.1)]. Efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate [see Adverse Reactions (6.2) and Use in Specific Populations 8.7)]. Monitoring of liver enzymes before and during treatment is recommended for all patients [see Dosage and Administration 2.1)]. Consider discontinuing efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation [see Adverse Reactions 6.1)]. 5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions. The concomitant use of efavirenz, emtricitabine and tenofovir disoproxil fumarate and other drugs may result in potentially significant drug interactions [see Contraindications 4) and Drug Interactions 7.3)], some of which may lead to: Loss of therapeutic effect of concomitant drug or efavirenz, emtricitabine and tenofovir disoproxil fumarate and possible development of resistance. Possible clinically significant adverse reaction from greater exposures of efavirenz, emtricitabine and tenofovir disoproxil fumarate or concomitant drug. QTc prolongation has been observed with the use of EFV [see Drug Interactions 7.1) and Clinical Pharmacology 12.2)]. Consider alternatives to efavirenz, emtricitabine and tenofovir disoproxil fumarate when coadministered with drug with known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes. See Table for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during efavirenz, emtricitabine and tenofovir disoproxil fumarate therapy and review concomitant medications during efavirenz, emtricitabine and tenofovir disoproxil fumarate therapy [see Dosage and Administration 2.5), Contraindications 4), and Drug Interactions 7)]. 5.5 Psychiatric Symptoms. Serious psychiatric adverse experiences have been reported in patients treated with EFV, component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. In controlled trials of 1,008 subjects treated with regimens containing EFV for mean of 2.1 years and 635 subjects treated with control regimens for mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among subjects who received EFV or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as group in multifactorial analysis of data from Study AI266006 (006, NCT00002410), Phase randomized, open-label trial of EFV-containing regimens versus controls in 1,266 subjects (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with EFV zidovudine lamivudine, EFV indinavir, and indinavir zidovudine lamivudine, respectively), treatment with EFV was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at trial entry; similar associations were observed in both the EFV and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the trial for both EFV-treated and control-treated subjects. One percent of EFV-treated subjects discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although causal relationship to the use of EFV cannot be determined from these reports. Postmarketing cases of catatonia have also been reported and may be associated with increased EFV exposure. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of EFV, and if so, to determine whether the risks of continued therapy outweigh the benefits [see Adverse Reactions 6)]. 5.6 Nervous System Symptoms. Fifty-three percent (531/1,008) of subjects receiving EFV in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens. These symptoms included dizziness (28.1% of the 1,008 subjects), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild to moderate (50.7%); symptoms were severe in 2.0% of subjects. Overall, 2.1% of subjects discontinued therapy as result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first to weeks of therapy. After weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in subjects treated with regimens containing EFV and from 3% to 5% in subjects treated with control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms [see Warnings and Precautions 5.5)] Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration 2.2)]. Analysis of long-term data from Study 006 showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among EFV-treated subjects were generally similar to those in the indinavir-containing control arm. Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning EFV therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased EFV levels despite standard dosing of EFV. Patients presenting with signs and symptoms of serious neurologic adverse experiences should be evaluated promptly to assess the possibility that these events may be related to EFV use, and whether discontinuation of efavirenz, emtricitabine and tenofovir disoproxil fumarate is warranted. Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate should be alerted to the potential for additive central nervous system effects when efavirenz, emtricitabine and tenofovir disoproxil fumarate is used concomitantly with alcohol or psychoactive drugs. Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery. 5.7 New Onset or Worsening Renal Impairment. Emtricitabine and tenofovir are principally eliminated by the kidney; however, EFV is not. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Adverse Reactions 6.2)]. Prior to initiation and during use of efavirenz, emtricitabine and tenofovir disoproxil fumarate, on clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min). Efavirenz, emtricitabine and tenofovir disoproxil fumarate should be avoided with concurrent or recent use of nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions 7.2)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. 5.8 Embryo-Fetal Toxicity. Efavirenz may cause fetal harm when administered during the first trimester of pregnancy. Advise adults and adolescents of childbearing potential who are receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate to avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and for 12 weeks after discontinuation [see Dosage and Administration 2.1), Use in Specific Populations 8.1, 8.3)]. 5.9 Bone Loss and Mineralization Defects. Bone Mineral Density In clinical trials in HIV-1 infected adults, TDF (a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin levels were also higher in subjects receiving TDF. Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis-B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained. Mineralization Defects Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with TDF use [see Adverse Reactions 6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products [see Warnings and Precautions 5.7)]. 5.10 Convulsions. Convulsions have been observed in adult and pediatric patients receiving EFV, generally in the presence of known medical history of seizures. Caution must be taken in any patient with history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels [see Drug Interactions 7.3)]. 5.11 Lactic Acidosis/Severe Hepatomegaly with Steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF and FTC, components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, alone or in combination with other antiretrovirals. Treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).. 5.12 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, Guillain-Barre syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.13 Fat Redistribution. Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, has been observed in patients receiving antiretroviral therapy, including EFV. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.